Triage by methylation-marker testing versus cytology in women who test HPV-positive on self-collected cervicovaginal specimens (PROHTECT-3): a randomised controlled non-inferiority trial

Verhoef, Viola M.J.; Bosgraaf, Remko P.; Kemenade, Folkert J. van; Rozendaal, Lawrence; Heideman, Daniëlle A.M.; Hesselink, Albertus T.; Bekkers, Ruud L.M.; Steenbergen, Renske D.M.; Massuger, Leon F.A.G.; Melchers, Willem J. G.; Bulten, Johan; Overbeek, L.I.H.; Berkhof, Johannes; Snijders, Peter J.F.; Meijer, Chris J.L.M.

doi:10.1016/s1470-2045(14)70019-1

Cited by 144 publications

(186 citation statements)

References 34 publications

Supporting

Mentioning

177

Contrasting

Unclassified

Order By: Relevance

“…Moreover, prior knowledge of hrHPV-positivity influences cytology reading, which may result in an increase of false-positive referrals with simultaneously higher costs for the healthcare system [47–49]. Recent clinical validation studies in screening populations have shown that DNA methylation markers provide a good alternative for cytology [14,50–54]. …”

Section: Discussionmentioning

confidence: 99%

Host-cell DNA methylation patterns during high-risk HPV-induced carcinogenesis reveal a heterogeneous nature of cervical pre-cancer

et al. 2018

View full text Add to dashboard Cite

Cervical cancer development following a persistent infection with high-risk human papillomavirus (hrHPV) is driven by additional host-cell changes, such as altered DNA methylation. In previous studies, we have identified 12 methylated host genes associated with cervical cancer and pre-cancer (CIN2/3). This study systematically analyzed the onset and DNA methylation pattern of these genes during hrHPV-induced carcinogenesis using a longitudinal in vitro model of hrHPV-transformed cell lines (n = 14) and hrHPV-positive cervical scrapings (n = 113) covering various stages of cervical carcinogenesis. DNA methylation analysis was performed by quantitative methylation-specific PCR (qMSP) and relative qMSP values were used to analyze the data. The majority of genes displayed a comparable DNA methylation pattern in both cell lines and clinical specimens. DNA methylation onset occurred at early or late immortal passage, and DNA methylation levels gradually increased towards tumorigenic cells. Subsequently, we defined a so-called cancer-like methylation-high pattern based on the DNA methylation levels observed in cervical scrapings from women with cervical cancer. This cancer-like methylation-high pattern was observed in 72% (38/53) of CIN3 and 55% (11/20) of CIN2, whereas it was virtually absent in hrHPV-positive controls (1/26). In conclusion, hrHPV-induced carcinogenesis is characterized by early onset of DNA methylation, typically occurring at the pre-tumorigenic stage and with highest DNA methylation levels at the cancer stage. Host-cell DNA methylation patterns in cervical scrapings from women with CIN2 and CIN3 are heterogeneous, with a subset displaying a cancer-like methylation-high pattern, suggestive for a higher cancer risk.

show abstract

Section: Discussionmentioning

confidence: 99%

Host-cell DNA methylation patterns during high-risk HPV-induced carcinogenesis reveal a heterogeneous nature of cervical pre-cancer

et al. 2018

View full text Add to dashboard Cite

show abstract

“…HPV-typing and other molecular triaging methods of the self-taken samples could enable more individualistic follow-up schemes in the future and increase the PPV of a referral to colposcopy. 34,35 The effect of a second reminder by letter has not been studied in Finland, but experience from other countries shows that it is not as effective as using self-sampling as a second reminder. 13,25 Further, feedback received from women during the study suggests that sending an invitation letter for the third time within 1 year might cause more annoyance than offering the self-sampling option which provides a clearly different approach to screening and might appeal to women reluctant to take part in traditional screening.…”

Section: Discussionmentioning

confidence: 99%

Improving cervical cancer screening attendance in Finland

Virtanen

Anttila

Luostarinen

et al. 2014

Intl Journal of Cancer

View full text Add to dashboard Cite

High attendance is essential to cervical cancer screening results. Attendance in the Finnish program is currently at 70%, but extensive opportunistic screening occurs beside the organized. A shift from opportunistic to organized screening is imperative to optimize the costs and impact of screening and minimize potential harms. We evaluated the effect of reminder letters (1st reminder) and self-sampling test (2nd reminder) on program attendance. The study population consisted of 31,053 screening invitees in 31 Finnish municipalities. 8,284 non-attendees after one invitation received a reminder letter and 4,536 further non-attendees were offered a self-sampling option. Socioeconomic factors related to participation were clarified by combining screening data to data from Statistics Finland. Reminder letters increased participation from 72.6% (95% CI 72.1, 73.1) to 79.2% (95% CI 78.8, 79.7) and self-sampling further to 82.2% (95% CI 81.8, 82.7). Reminder letters with scheduled appointments resulted in higher increase than open invitations (10 vs. 6%). Screening of original non-attendees increased the yield of CIN31 lesions by 24%. Non-attendance was associated with young age, immigrant background, lower education level and having never been married. We showed that a total attendance of well over 80% can be achieved within an organized program when the invitational protocol is carefully arranged.Good coverage amongst those at risk and high attendance within the cervical cancer screening program are of paramount importance to results. In Finland, a substantial proportion of cancer incidence and especially mortality among women in screening ages 30-60 years is seen among nonattendees. 1,2 Attendance in the program is currently 70% with a slightly decreasing trend (www.cancerregistry.fi).In addition to personal invitations to screening, prebooked appointments in invitation letters and reminders sent to non-attendees increase screening attendance. 3-12 Selfsampling for high risk human papillomavirus (hrHPV) DNA testing helps to further increase attendance among women who are not reached by the routine screening program. [11][12][13][14][15][16][17][18][19] The ability (relative sensitivity) to detect moderate cervical intraepithelial neoplasias or worse (CIN21) of hrHPVtesting on self-taken samples has been shown to be somewhat lower than that of hrHPV-testing on clinician-based samples, but similar or even more sensitive to a Pap-smear, depending on the cytological threshold. 20 The main aim of this study was to study the effect of reminder letters (1st reminder) and self-sampling tests (2nd reminder) as means to increase attendance within the routine cervical cancer screening programme in a wide setting of Finnish municipalities. Screening results among the attendees and original non-attendees were also explored.We further studied the socioeconomic characteristics of nonparticipants to routine screening to find groups that should be in the focus when planning interventions to increase attendance. Material and MethodsIn...

show abstract

“…Fear or embarrassment related to the cervical scraping procedure and other practical reasons related to visiting a physician [115] restrain about 30% of eligible women from participation in cytology-based screening in the Netherlands [116]. This problem, which also exists in other industrialized countries, could be circumvented by offering these women a hrHPV-test on self-sampled material [103,117], which has been shown to be a feasible alternative to hrHPV-testing on cervical scrapes [118,119]. However, the use of Pap cytology or p16/Ki-67 dual-stained cytology for triage would still require a visit to a physician.…”

Section: Expert Commentarymentioning

confidence: 99%

“…Therefore, host cell DNA methylation analysis might be of value as a marker for the detection of cervical (pre)cancer among hrHPV-positive women [32,92]. A variety of methylation markers has been studied in clinical cohorts of hrHPVpositive women [51,80,81,96,97,99,[102][103][104][105][106]. In general, these studies were cross-sectional or had a short-term follow-up and the majority of studies were performed in nonscreening cohorts.…”

mentioning

confidence: 99%

“…In contrast to most candidate triage markers in hrHPV-positive women, host cell DNA methylation analysis has been shown feasible in self-sampled material. In a large randomized controlled trial among hrHPV-positive screening non-attendees (n = 1019) [103], combined methylation analysis of MAL/mir124-2 on self-sampled cervicovaginal lavage material yielded a ≥CIN3 sensitivity of 73.5% and a specificity of 47.2% (Table 2) [80,103]. Combined methylation analysis of FAM19A4 and mir124-2 was evaluated in a subset of these hrHPV-positive non-attendees using self-collected lavages (n = 389), as well as hrHPV-positive non-attendees from another cohort who submitted self-collected brushes (n = 254) [81].…”

mentioning

confidence: 99%

See 1 more Smart Citation

Management of high-risk HPV-positive women for detection of cervical (pre)cancer

Luttmer

Strooper

Steenbergen

et al. 2016

Expert Review of Molecular Diagnostics

Self Cite

View full text Add to dashboard Cite

Introduction: Primary HPV-testing has been shown to provide a superior detection of women at risk of cervical (pre)cancer compared to cytology-based screening. However, as most high-risk HPV infections are harmless, additional triage testing of HPV-positive women is necessary to identify those with cervical (pre)cancer. In this paper, we compare the performance, advantages and limitations of clinically relevant available triage strategies for HPV-positive women. Areas covered: Many different colposcopy triage strategies, comprising both microscopy-based and molecular (virus/host-related) markers, have been suggested: Pap cytology, p16/Ki-67 dual-stained cytology, HPV16/18 genotyping, viral DNA methylation and host cell DNA methylation. Literature search was limited to triage strategies that have achieved at least phase 2 of the five-phase framework for biomarker development and studies including large cohorts (≥100 hrHPV-positive women). Triage markers were stratified by sample type (cervical scrape, self-collected sample) and by study population (screening, non-attendee, referral). Expert commentary: At present, repeat Pap cytology and Pap cytology combined with HPV16/18 genotyping are the only triage strategies that have been robustly shown to be ready for implementation. Other strategies such as p16/Ki-67 dual-stained cytology and host cell DNA methylation analysis, with or without additional HPV16/18 genotyping, are attractive options for the near future. ARTICLE HISTORY

show abstract

Triage by methylation-marker testing versus cytology in women who test HPV-positive on self-collected cervicovaginal specimens (PROHTECT-3): a randomised controlled non-inferiority trial

Cited by 144 publications

References 34 publications

Host-cell DNA methylation patterns during high-risk HPV-induced carcinogenesis reveal a heterogeneous nature of cervical pre-cancer

Host-cell DNA methylation patterns during high-risk HPV-induced carcinogenesis reveal a heterogeneous nature of cervical pre-cancer

Improving cervical cancer screening attendance in Finland

Management of high-risk HPV-positive women for detection of cervical (pre)cancer

Contact Info

Product

Resources

About